Leishmaniasis

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The disease is spread by the bite of infected female phlebotomine sandflies.

More than 90 of the 1,000 or so sandfly species are known to transmit the disease. Different species cause different clinical forms of the disease in various parts of the world.

The protozoan multiplies in the insect vector and is then inoculated into another mammalian recipient, possibly a human. There it is engulfed by macrophages but may survive and even replicate inside them.

The most common affected areas are the Mediterranean, India, Bangladesh, Brazil and Sudan.

The cutaneous form presents with skin ulcers, and the mucocutaneous form with ulcers of the skin and also the mucous membranes of the mouth and nose. The visceral form is more generalised, especially in the reticuloendothelial system.

Kala azar is a Hindi word applied to the visceral form.

Epidemiology

The epidemiology of leishmaniasis is influenced by several things:

The characteristics of the parasite species.

The local ecological characteristics of the transmission sites.

Current and past exposure of the human population to the parasite.

Human behaviour.

Incidence

The World Health Organization (WHO) reports an estimated 300,000 new cases of visceral leishmaniasis (VL) with 20,000 to 30,000 deaths annually.[1]

An estimated 1 million new cases a year of cutaneous and mucocutaneous leishmaniasis occur annually.[2]

310 million people are said to live at risk of VL in six countries worldwide: Bangladesh, Ethiopia, Brazil, India, South Sudan and Sudan.[2]

Cases are occasionally seen in the UK, usually resulting from travel to the Mediterranean.

The disease affects the poorest people on the planet, and is associated with malnutrition, population displacement, poor housing, a weak immune system and lack of resources.

Prevalence

More than 12 million people in 88 countries are known to be infected but many cases are asymptomatic. Furthermore, reporting is far from complete in many areas and true numbers are almost certainly very much higher.

The male to female ratio is about 2:1, probably due to greater exposure of women to places where there is a risk of sandfly bites.

Epidemiology by area

Mediterranean Basin

VL is the main form, occurring in rural areas, mountainous villages and some peri-urban areas where dogs may harbour parasites.

Southeast Asia

VL is the main form, and transmission is mainly in low-altitude rural areas (<600 m above sea level) with high rainfall and humidity, temperature range 15-38°C, abundant vegetation, subsoil water and alluvial soil. It is most common in farming villages where houses have mud walls and earthen floors and cattle and humans live in close proximity.

CL is the most common form and the disease reservoir is mainly in humans and rodents. Large outbreaks occur during times of civil unrest/war, and population migrations, when non-immune populations encounter the vectors. Agricultural projects and irrigation schemes which move people in also increase the prevalence.

Americas

Both VL and CL are seen. There are multiple shades of variation in parasites, immunity clinical manifestations and response to therapy in this part of the work.

Risk factors

Usually transmission is by the bite of the female sandfly. In some areas there are animal reservoirs but in others humans are the only mammalian source.

Risk factors include those which increase sandfly breeding and nesting and those which increase their access to non-immune humans:

Poor socio-economic conditions.

Malnutrition: diets lacking protein energy, iron, vitamin A and zinc increase the risk that infection will progress to kala azar.

Mass population movements, moving non-immune people into endemic areas.

Deforestation has a similar effect; moving people into deforested areas inhabited by sandflies can rapidly increase cases.

Environmental changes: urbanisation, and the incursion of agriculture into forested areas, increasing sandfly contact, bringing in non-immune people and livestock.

Climate change: leishmaniasis is affected by changes in rainfall, temperature and humidity. Global warming and land degradation can not only have profound effects on sandfly populations, but small changes in temperature can expand the geographical area in which the parasite is able to replicate, allowing increase in endemic areas.

Drought, famine, flood and other natural disasters cause population movements and breakdown of infrastructure associated with all the risk factors above.

Presentation will vary significantly according to the species of infection and the location in the world. Broadly speaking there are three main forms (visceral, cutaneous and mucocutaneous, but these are general descriptive terms with some overlap, and with some further classifications beyond them.

Visceral leishmaniasis (VL)

VL is fatal if left untreated.

It can occur in both Old and New World disease.

It is highly endemic in the Indian subcontinent and East Africa.

90% of new cases occur in Bangladesh, Brazil, Ethiopia, India, South Sudan and Sudan.

In Africa a cutaneous nodule may precede systemic disease by weeks or months, but is rare in other parts of the world.

There is infection of liver, spleen and bone marrow, causing the classical features of:

Night sweats, weakness and anorexia, which are typical.

Fever.

Weight loss.

Hepatomegaly (can be marked).

Splenomegaly (often enormous).

Anaemia and pancytopenia (can lead to death from haemorrhage or infection).

Hypergammaglobulinaemia.

Dark pigmentation of the skin is uncommon but the name kala azar is Hindi for black fever.

In MCL, dental scrapings or mucosal granuloma biopsy can be used but parasites may be difficult to find.

In visceral disease, bone-marrow aspiration is the safest technique, although splenic aspiration may be used in difficult cases. Splenic aspiration has a higher sensitivity but greater risks.

Contra-indications to splenic aspiration include low platelet count, abnormal prothrombin time, and a spleen palpable 4 cm or more below the costophrenic angle.

Liver biopsy and lymph node dissection may also provide material.

Various serological tests are available, but most cutaneous cases do not develop a significant antibody response. They are attractive as they require fewer resources than tissue diagnosis.[4]

There are two serological tests under investigation: direct agglutination test (DAT) and Ks30 dipstick. Both appear to perform well in a meta-analysis.[5] However, their main downside is that they remain positive for years after successful therapy. Other tests are also under design.

In CL most usual blood parameters will be normal but in VL there will be pancytopenia on FBC, elevated globulin and slight abnormality of LFTs. Prothrombin time should be normal.

It is impossible to generalise regarding the pharmaceutical management of leishmaniasis, as treatment depends on many things, including geographical location, infecting species, immune status of host and type of disease.

Some approaches/regimens are effective only against certain species and strains of Leishmania and only in particular geographical regions.

There is a lack of evidence base for treatment, and where there is evidence it cannot be extrapolated to other areas and species.

Special groups (such as young children, elderly persons, pregnant/lactating women, and persons who are immunocompromised or who have other comorbidities) may need different medications or dosage regimens.

To treat or not?

Leishmaniasis is a treatable and curable disease.

Treatment depends upon type of disease, parasite species and geographical location.

In VL the prognosis is so much worse that treatment is required.

For VL, new formulations, therapeutic switching, and the potential for combinations of established drugs have improved treatment in India, but not in East Africa.

In the CL types that heal spontaneously the question is whether any treatment should be offered, especially as treatment can be quite toxic.

New World CL may progress to mucocutaneous disease and so should be adequately treated. Old World CL may be left alone or treated if lesions are slow to heal or disfiguring.[9]

A significant reduction in price negotiated by the WHO with the producers was followed in 2012 by a donation of 50,000 treatments. However, several ampoules are required for a single-course treatment, and adverse events and temperature stability remain

Like all VL treatments there are regional differences in response rates.

Paromomycin

Over 50 years ago, the aminoglycoside paromomycin was shown to possess anti-leishmanial activity.

Trials in India suggest 94% effectiveness for a single course, although trials in Africa suggest lower efficacy.

The drug is cheaper than amphotericin, and reasons for the slowness in uptake in India are unclear.

Its current main use is with stibogluconate as a treatment for VL in Africa.

Fluconazole

Oral fluconazole or itraconazole appears effective in Leishmania major and Leishmania tropica.

Pentamidine

This is a second-line agent used in the Americas, whose mode of action is not well understood. It has a tendency to toxic side effects. Early trials showed promise in CL.[15]

Topical treatment

Topical treatment is recommended for localised disease and options include injection of antimonials into the border of the lesion, cryosurgery, ultrasound-induced local hyperthermia, excision, topical 15% paromomycin sulfate/12% methylbenzethonium chloride in white paraffin.[16] Topical treatments must penetrate the dermis.

Other treatments

Ketoconazole, itraconazole, fluconazole, allopurinol, and dapsone are all less effective than the previously mentioned drugs.

In VL, attention should also be paid towards adequate nutrition to enhance the immune system.

In mucocutaneous disease, plastic surgery may be required.

Other injectable, oral and topical drugs have not been consistently effective.

Summary of treatment

For VL in India, South America and the Mediterranean, liposomal amphotericin as a single dose is usually recommended.

In Africa, for VL, Leishmania donovani is less susceptible to amphotericin, miltefosine and paromomycin as compared to the Indian strains, and a combination of pentavalent antimony compounds and paromomycin delivered over 17 days is recommended.

Liposomal amphotericin is the recommended regimen in the Mediterranean region and South America. It is also the treatment of choice for HIV-VL co-infection.

Miltefosine is effective against both VL and CL. It is well tolerated although it may be teratogenic in the first trimester. It appears ineffective against L. major and Leishmania braziliensis.

A number of topical treatments may be used for cutaneous leishmaniasis. Which treatments are effective depends on the strain. they include topical paromomycin, topical pentamidine.

Treatment of CL should be decided by the clinical lesions, etiological species and its potential to develop into mucosal leishmaniasis.

Prognosis

In VL about 90% of patients will improve whilst 10% will die. As they improve they become afebrile, blood parameters improve and the spleen shrinks.

Between 5% and 10% of those cured will relapse within six months.

Untreated VL has a mortality rate of between 75% and 95%.

Malnutrition and tuberculosis are complications.

Prevention and control

This needs a combination of interventions, as transmission occurs in a complex biological system in which behaviour of human, host, parasite, vector and environment are involved. Strategies include:

Early diagnosis and treatment to reduce complications including transmission.

Avoid being bitten by sandflies by using repellant, long sleeves and trousers and mosquito nets.

Effective disease surveillance.

Control of reservoir hosts where appropriate, although this needs to be tailored to the local situation.

Education of the community on both prevention and early diagnosis.

Improving access to treatment.

No vaccine is yet available but several potential vaccines are being developed.

There is an urgent need for exploratory studies with short-course, highly efficient treatment regimens such as combination therapy for all the endemic regions of VL. Shorter and more acceptable regimens are needed.[11]

Treatment of CL remains one of the neglected areas of leishmaniasis as data are scarce.

Historical aspects

Old World CL, or oriental sore, has been described in texts dating back to 1500-2500 BC. Arab physicians provided more detailed descriptions in the 10th century.

James Homer Wright (1869-1928), American pathologist, is generally credited with identification of the parasite.

In the Americas there is evidence of CL in pre-Inca pottery depicting skin lesions and deformed faces, dating back to the first century AD.

Old World VL, kala azar, was first described in 1824 in what is now Bangladesh, and the parasite, L. donovani, was discovered by Leishman and Donovan independently in 1900.

Sir William Leishman (1865-1926), Director General of the Royal Army Medical Corps, was a Glaswegian, and was more famous at the time for his work on an antityphoid vaccine, which successfully protected troops in World War I. He also developed his eponymous stain for the staining of malaria, trypanosomes, and other blood parasites. It was in his honour that the group of diseases caused by trypanosomes was renamed leishmaniasis.

Charles Donovan was Professor of Physiology at Madras University.

The identification of the vector involved took much longer, and it was not until 1921 that proof of transmission by sandflies was made. This was followed by proof of infection via the bite of the sandfly in 1941.

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